Pain and depression are common and often occur in the same patient. Over 75% of patients with depression suffer from pain symptoms and between 30-60% of pain patients report significant depressive symptoms. Moreover, the comorbidity between pain and depression contributes significantly to poorer outcomes and increased cost of treatment. This raises the key question: "why people experience more pain when they are depressed? Surprisingly, little is known about the pathophysiology of the interaction between pain and depression. The goal of this exploratory grant proposal is to bring these areas of research together to address the question, "do depression and pain share common neural substrates?" We propose to use Functional Magnetic Resonance Imaging (fMRI) with an experimental pain paradigm in individuals with current Major Depressive Disorder (MDD), as well as healthy comparison subjects. We will examine behavior and brain activity underlying anticipation and processing of aversive painful stimulus. We will use pain stimuli, which are processed via the spinothalamic pathway, to examine the integrity of the top-down pain modulation and hypothesize that altered activation of insula and anterior cingulate in subjects with MDD reflects altered interoception, i.e. the physiological condition of the entire body. The specific aims of this proposal are: 1) To assess sensory and affective responses to pain in subjects with current MDD. 2) To determine which neural substrates underlie anticipation and processing of painful stimulus, as well as the effects of simple distraction on these processes in subjects with current MDD. There are several important implications of this research. By measuring altered pain processing in depressed individuals, we will be able to (1) quantify the degree to which pain is abnormally processed; (2) link pain processing to the activation status of specific neural substrates; (3) suggest treatment interventions that are aimed to altered the brain activation of the proposed neural substrates; (4) develop a neurobiological basis for altered pain processes; and (5) utilize these findings for the development of biomarkers to monitor treatment outcomes in the future. Pain and depression are common and often co-occur in the same patient. This co-morbidity contributes significantly to poorer outcomes and increased cost of treatment and understanding the pathophysiology of pain-depression interaction by examining the neurobiology of pain processes in patients with depression will elucidate how depression alters one's reaction to stress. Identifying the mechanism of the aberrant response to stress in depressed individuals may identify neural substrates that predict symptom formation and can potentially serve as biomarkers for future therapeutic intervention. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]